Our recent double blind clinical trials demonstrated that ketamine (an NMDA antagonist) produced rapid onset, robust, and long-pasting antidepressive actions in the patients who are resistant to typical antidepressant treatment. We have hypothesized that targeting AMPA/NMDA receptor throughput is an effective strategy for rapid relief of depression symptoms. To further test the AMPA/NMDA throughput hypothesis and to develop new medication based on this ketamine phenomenon, we conducted a series of animal experiments. We found that subanesthetic doses of ketamine treatment produced rapid onset antidepressant-like effects in two behavioral paradigms, the learned helpless test and the forced swim test. The effects lasted at least more than a week after a single drug administration. MK-801 (dizocilpine) and Ro25-6981, a NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Animals treated with ketamine in a similar regiment to the learned helpless test performed well on passive avoidance tests, thus the antidepressant-like effects of ketamine in animal is unlikely due to learning and memory deterioration associated with ketamine use. Pre-treatment with NBQX, an AMPA receptor antagonist, blocked ketamine-, MK-801- and Ro25-6981-induced immobility reductions in the forced swim test, indicating the antidepressant-like effects of these agents require AMPA throughput. Ketamine altered GluR1 phosphorylation in hippocampal tissues from ketamine treated animals, the effects was also blocked by NBQX pretreatment. Taken together, our animal findings strongly support the involvement of AMPA receptors in ketamine_s antidepressant-like action and the AMPA/NMDA throughput strategy to develop novel antidepressive agents. Future studies are required to further elucidate the receptor subtype(s) and the brain region(s) involved in this ketamine antidepressant-like action.